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Background <p>Corosolic acid (CA) and its derivatives have shown promise as anticancer agents, but their effectiveness against resistant cancer types remains underexplored. Organelle-targeted drug delivery is a promising approach to enhance therapeutic efficacy and reduce side effects.</p> Methods <p>A mitochondria-targeted prodrug, CA-TPP, was synthesized using an esterase-responsive phenolic ester bond, which enables the in situ release of CA within the mitochondria. The therapeutic efficacy of CA-TPP was assessed both in vitro (using DU145 cells) and in vivo. RNA sequencing was employed to investigate the molecular mechanisms, particularly focusing on the PINK1/Parkin-mediated mitophagy pathway.</p> Results <p>CA-TPP significantly reduced the required treatment dose of CA by 75%, maintaining its anticancer activity. In DU145 cells, CA-TPP induced cell death through the mitochondrial apoptosis pathway. RNA sequencing revealed that CA-TPP activated apoptosis through PINK1/Parkin-mediated mitophagy. Inhibition of mitophagy via PINK1 shRNA alleviated the cytotoxic effects of CA-TPP, confirming the role of mitophagy in its mechanism. Additionally, CA-TPP treatment resulted in elevated ROS production, leading to mitochondrial apoptosis and mitophagy.</p> Conclusions <p>The CA-TPP prodrug strategy enhances the specificity and anti-tumor effects of corosolic acid, offering a promising approach for targeted cancer therapy. This work opens new possibilities for mitochondria-targeted cancer treatments with reduced drug dosages. This study did not involve clinical trials, and thus trial registration is not applicable.</p> Graphical Abstract <p></p>

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Mitochondria in situ releasing corosolic acid enhanced antitumor effects via activating mitophagy in castration-resistant prostate cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Jiaxin Zhang,
  • Hang Zhang,
  • Bin Fang,
  • Haoqin Li,
  • Limin Wang,
  • Yi Liu,
  • Tao Shao,
  • Haixiao Fang,
  • Bo Peng,
  • Wei Zhang,
  • Hua Bai,
  • Bo Ma,
  • Lin Li

摘要

Background

Corosolic acid (CA) and its derivatives have shown promise as anticancer agents, but their effectiveness against resistant cancer types remains underexplored. Organelle-targeted drug delivery is a promising approach to enhance therapeutic efficacy and reduce side effects.

Methods

A mitochondria-targeted prodrug, CA-TPP, was synthesized using an esterase-responsive phenolic ester bond, which enables the in situ release of CA within the mitochondria. The therapeutic efficacy of CA-TPP was assessed both in vitro (using DU145 cells) and in vivo. RNA sequencing was employed to investigate the molecular mechanisms, particularly focusing on the PINK1/Parkin-mediated mitophagy pathway.

Results

CA-TPP significantly reduced the required treatment dose of CA by 75%, maintaining its anticancer activity. In DU145 cells, CA-TPP induced cell death through the mitochondrial apoptosis pathway. RNA sequencing revealed that CA-TPP activated apoptosis through PINK1/Parkin-mediated mitophagy. Inhibition of mitophagy via PINK1 shRNA alleviated the cytotoxic effects of CA-TPP, confirming the role of mitophagy in its mechanism. Additionally, CA-TPP treatment resulted in elevated ROS production, leading to mitochondrial apoptosis and mitophagy.

Conclusions

The CA-TPP prodrug strategy enhances the specificity and anti-tumor effects of corosolic acid, offering a promising approach for targeted cancer therapy. This work opens new possibilities for mitochondria-targeted cancer treatments with reduced drug dosages. This study did not involve clinical trials, and thus trial registration is not applicable.

Graphical Abstract